Inhibiting Mg Diffusion and Evaporation by Forming Mg-Rich Reservoir at Grain Boundaries Improves the Thermal Stability of N-Type Mg3 Sb2 Thermoelectrics.
N-type Mg3 Sb2 -based thermoelectric materials show great promise in power generation due to their mechanical robustness, low cost of Mg, and high figure of merit (ZT) over a wide range of temperatures. However, their poor thermal stability hinders their practical applications. Here, MgB2 is introduced to improve the thermal stability of n-type Mg3 Sb2 . Enabled by MgB2 decomposition, extra Mg can be released into the matrix for Mg compensation thermodynamically, and secondary phases of Mg─B compounds can kinetically prevent Mg diffusion along grain boundaries. These synergetic effects inhibit the formation of Mg vacancies at elevated temperatures, thereby enhancing the thermal stability of n-type Mg3 Sb2 . Consequently, the Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 (MgB2 )0.03 sample exhibits negligible variation in thermoelectric performance during the 120-hour continuous measurement at 673 K. Moreover, the ZT of n-type Mg3 Sb2 can be maintained by adding MgB2 , reaching a high average ZT of ≈1.1 within 300-723 K. An eight-pair Mg3 Sb2 -GeTe-based thermoelectric device is also fabricated, achieving an energy conversion efficiency of ≈5.7% at a temperature difference of 438 K with good thermal stability. This work paves a new way to enhance the long-term thermal stability of n-type Mg3 Sb2 -based alloys and other thermoelectrics for practical applications.


Platelet-activating factor (PAF) in internal jugular venous blood of migraine without aura patients assessed during migraine attacks.
The aim of the study was to verify the production of PAF and the activity of PAF acetyl-hydrolase (PAF-AH), the enzyme involved in the catabolism of this phospholipid mediator, in migraine attacks. Their levels were determined during migraine crises in serial samples of internal jugular venous blood taken from five migraine patients without aura, who were admitted to the hospital during the crises. Internal jugular venous blood samples were taken immediately after catheter insertion at 1, 2, and 4 h after attack onset, and within 2 h from its cessation. PAF was purified by high-performance liquid chromatography (HPLC) and determined by radioimmunoassay method. The enzymatic activity of PAF-AH was measured by reverse-phase HPLC, based on the derivatization with 7-diethylaminocoumarin-3-carbonylazide. In the internal jugular venous blood of migraine patients without aura (MO), an increase was observed in PAF levels, which was already evident at the time of catheter insertion (885.6 +/- 82.8) and at the first hour (868.4 +/- 65.24) (ANOVA: P < 0.0001). PAF levels remained elevated through the second (746.8 +/- 82.95), fourth (700.6 +/- 34.93) and sixth hours (644.4 +/- 42.85), and then decreased at the end of the attack, reaching levels significantly lower than those measured at the time of catheter insertion (565.5 +/- 38.34). The activity of PAF-AH showed an opposite trend with higher values at the first hour and significantly lower values at the second and fourth hours from the beginning of the migraine attack (ANOVA: P < 0.02). The increased production of PAF may account for persistent platelet activation during migraine crises, even in the presence of an increased production of nitric oxide (NO) end-products which, on the other hand, should instead intervene in counteracting and limiting platelet activation. Potential sources of PAF production are the endothelial cells from cerebral vessels, stimulated by trigeminal neuropeptides, platelets themselves, and mast cells, as suggested by the neurogenic inflammation model.


One step hydrothermal synthesis and characterization of moss like MWCNT-Bi2S3 nanomaterial for solid phase extraction of copper.
The present work was designed with the aim to one step simple hydrothermal synthesis of moss like MWCNT-Bi2S3 nanomaterial as solid phase extraction sorbent for separation, preconcentration and determination of copper in tobacco and food samples. Cu(II) ions was strongly retained on the MWCNT-Bi2S3 nanomaterial at the pH 7.0 and was successfully desorbed by using 1.5mL of 4M HNO3. The copper concentration in eluent was determined by flame atomic absorption spectrometer. The certified reference material (NC SZC 73033 Scallion) was analyzed for the verification and accuracy of the proposed method. This work was interpreted statistically and found the analytical performance of the proposed method which consist of preconcentration factor (20), limit of quantification (13.1µgL-1) and relative standard deviation (2.2%), respectively. It was concluded that this method was applied for the detection of copper from different types of tobacco and food samples successfully.


Psoriasis in pregnancy: challenges and solutions.
The available information about the effects of pregnancy on psoriasis and those of psoriasis on pregnancy is almost limited, despite the high frequency of the disease in the general population, as well as in women in reproductive years. Considering the existing evidence, pregnancy does not tend to have a negative influence on psoriasis, as in most women who experience a change in the severity and course of their psoriasis during pregnancy, the change is more likely to be reported as an improvement. This assumption can be applied more convincingly to plaque-type psoriasis, while an exception may be represented by generalized pustular psoriasis, which has been somehow linked to impetigo herpetiformis. Conflicting findings emerged from the few available studies that explored the effect of psoriasis on pregnancy outcomes. Recent studies found an association between moderate-to-severe psoriasis and some pregnancy complications, including pregnancy-induced hypertensive diseases, and have emphasized a trend toward a newborn with low birth weight in patients with psoriasis, especially in those suffering from severe forms. The safety profile during pregnancy is not completely known for many drugs used to treat psoriasis. Moisturizers and low- to moderate-potency topical steroids or ultraviolet B phototherapy represent the first-line therapy for pregnant patients. Many dermatologists may, however, recommend discontinuing all drugs during pregnancy, in consideration of medico-legal issues, and also taking into account that common forms of psoriasis do not compromise the maternal and fetal health. Anyway, for those women whose psoriasis improves during pregnancy, the interruption of any therapy for psoriasis can be a reasonable strategy. The objective of this paper was to review the most relevant literature data on psoriasis in pregnancy, trying to give concurrently practical information about clinical and prognostic aspects, as well as counseling and management.


Electrospun nylon nanofibers as effective reinforcement to polyaniline membranes.
This research demonstrates that a nylon nanofiber (NNF) mat can be an effective mechanical reinforcement to polyaniline (PANI) thin films. Nanofibers of ca. 250 nm diameter were produced by electrospinning of a nylon 6 solution in formic acid. Scanning electron microscopy showed that the solution impregnation method utilized was effective to embed the nanofibers into the PANI matrix. The effectiveness of NNFs as a mechanical reinforcement of a PANI thin film was assessed via dynamic mechanical analysis in tension mode. The as-cast PANI films displayed a tensile dynamic modulus, E', of ca. 0.65 GPa at room temperature. Scanning in the temperature showed that the PANI film has a usage temperature of up to about 80 degrees C, with this being limited by its glass transition temperature, and over this temperature range, the elastic modulus was nearly independent of the temperature. On the other hand, the PANI-NNF composite displayed a significantly higher tensile modulus at room temperature (1.1 GPa) and its usage temperature was extended up to just over 200 degrees C, with this being limited by the melting transition of nylon 6 (at 220 degrees C). The results therefore showed that the NNF mat increased the usage temperature of PANI films over 100 degrees C, opening up applications for PANI membranes.


Origin of the exotic blue color of copper-containing historical pigments.
The study of chemical factors that influence pigment coloring is a field of fundamental interest that is still dominated by many uncertainties. In this Article, we investigate, by means of ab initio calculations, the origin of the unusual bright blue color displayed by historical Egyptian Blue (CaCuSi4O10) and Han Blue (BaCuSi4O10) pigments that is surprisingly not found in other compounds like BaCuSi2O6 or CaCuO2 containing the same CuO4(6-) chromophore. We show that the differences in hue between these systems are controlled by a large red-shift (up to 7100 cm(-1)) produced by an electrostatic field created by a lattice over the CuO4(6-) chromophore from the energy of the 3z(2)-r(2) → x(2)-y(2) transition, a nonlocal phenomenon widely ignored in the realm of transition metal chemistry and strongly dependent upon the crystal structure. Along this line, we demonstrate that, although SiO4(4-) units are not involved in the chromophore itself, the introduction of sand to create CaCuSi4O10 plays a key role in obtaining the characteristic hue of the Egyptian Blue pigment. The results presented here demonstrate the opportunity for tuning the properties of a given chromophore by modifying the structure of the insulating lattice where it is located.


Facile Route to Rare Heterobimetallic Aluminum-Copper and Aluminum-Zinc Selenide Clusters.
Heterobimetallic aluminum-copper and aluminum-zinc clusters were prepared from the reaction of LAl(SeH)2 [1; L = HC(CMeNAr)2 and Ar = 2,6-iPr2C6H3] with (MesCu)4 and ZnEt2, respectively. The resulting clusters with the core structures of Al2Se4Cu4 and Al2Se4Zn3 exhibit unique metal-organic frameworks. This is a novel pathway for the synthesis of aluminum-copper and aluminum-zinc selenides. The products have been characterized by spectroscopic methods and single-crystal X-ray structural characterization.


[Indications for pharyngeal surgery in adult with sleep-disordered breathing patients].
We assessed the indications for pharyngeal surgery, including tonsillectomy and uvulopalatopharyngoplasty (UPPP) for patients with sleep-disordered breathing (SDB). The indications for surgery can be divided into two groups. In the first group, the indicated surgery is a radical treatment of SDB. The characteristics of this group were (1) grade 1 tonsillar hypertrophy, (2) bilateral (side to side type) oropharyngeal stenosis, as determined using a snoring sound test, and (3) no risk of facial disfiguration. In this group, the improvement in AHI (Apnea Hypopnea Index) was 76.2%, while the improvement in AI (Apnea Index) was 95.7%. In the second group, the treatment was designated as supplemental. The characteristics of this group were (1) bilateral oropharyngeal stenosis, (2) tonsillar hypertrophy larger than grade 2, and (3) unsuccessful treatment with NCPAP (Nasal Continuous Positive Airway Pressure) or oral appliances. In this group, the improvement in AHI was 50.7%, but, surgery remained an effective means of treating SDB.


The MAMP-Responsive MYB Transcription Factors MYB30, MYB55 and MYB110 Activate the HCAA Synthesis Pathway and Enhance Immunity in Rice.
Phenylpropanoids, including diverse compounds, such as monolignols and hydroxycinnamic acids (HCAAs), are essential for land plants to protect them against abiotic stresses, and create physical and chemical barriers to pathogen infection. However, the control of production of these compounds in response to pathogens has been poorly understood. Previously we showed that a MAMP- (microbe-associated molecular pattern) responsive MAPK (mitogen-activated protein kinase) cascade (MKK4-MPK3/MPK6) comprehensively induced the expression of cinnamate/monolignol synthesis genes in rice cells. Here, we identified three MYB proteins, MYB30, MYB55 and MYB110, which are transcriptionally induced by MAMP treatment, MAPK activation and pathogen inoculation. Induced expression of these MYB genes systematically and specifically induced a large part of the genes encoding enzymes in the cinnamate/monolignol pathway. Furthermore, induced expression of the MYB genes caused accumulation of ferulic acid, one of the HCAAs, and enhanced resistance to both fungal and bacterial pathogens in planta. In conclusion, MYB30, MYB55 and MYB110 are involved in the signal pathway between MAMP perception and cinnamate/monolignol synthesis, and have important roles for plant immunity.


Deletion between direct repeats in T7 DNA stimulated by double-strand breaks.
An in vitro system based on extracts of Escherichia coli infected with bacteriophage T7 was used to study genetic deletions between directly repeated sequences. The frequency of deletion was highest under conditions in which the DNA was actively replicating. Deletion frequency increased markedly with the length of the direct repeat both in vitro and in vivo. When a T7 gene was interrupted by 93 bp of nonsense sequence flanked by 20-bp direct repeats, the region between the repeats was deleted in about 1 out of every 1,600 genomes during each round of replication. Very similar values were found for deletion frequency in vivo and in vitro. The deletion frequency was essentially unaffected by a recA mutation in the host. When a double-strand break was placed between the repeats, repair of this strand break was often accompanied by the deletion of the DNA between the direct repeats, suggesting that break rejoining could contribute to deletion during in vitro DNA replication.


Photodetectors Based on Organic-Inorganic Hybrid Lead Halide Perovskites.
Recent years have witnessed skyrocketing research achievements in organic-inorganic hybrid lead halide perovskites (OIHPs) in the photovoltaic field. In addition to photovoltaics, more and more studies have focused on OIHPs-based photodetectors in the past two years, due to the remarkable optoelectronic properties of OIHPs. This article summarizes the latest progress in this research field. To begin with, the factors influencing the performance of photodetectors are discussed, including both internal and external factors. In particular, the channel width and the incident power intensities should be taken into account to precisely and objectively evaluate and compare the output performance of different photodetectors. Next, photodetectors fabricated on single-component perovskites in terms of different micromorphologies are discussed, namely, 3D thin-film and single crystalline, 2D nanoplates, 1D nanowires, and 0D nanocrystals, respectively. Then, bilayer structured perovskite-based photodetectors incorporating inorganic and organic semiconductors are discussed to improve the optoelectronic performance of their pristine counterparts. Additionally, flexible OIHPs-based photodetectors are highlighted. Finally, a brief conclusion and outlook is given on the progress and challenges in the field of perovskites-based photodetectors.


Failure of intertypic recombinant constructed from HSV-1 x HSV-2 virulent parents to induce ocular pathology.
An intertypic recombinant constructed from HSV-1 x HSV-2 parents was isolated which failed to induce any overt ocular pathology when inoculated onto the sacrificed cornea of four-week-old SJL/J mice. During the 24-48 hour post-infection period there was transient virus replication but by day 3 the infectious titer in the eye had dropped by greater than or equal to 10(4)-fold, and little or no virus could be recovered thereafter. When immunosuppressed (600 r) mice were infected corneally, virus clearance was delayed several days but again no obvious ocular pathology was seen, and no mice died. By contrast, infection of the cornea with either parent was followed by virus replication and development of clinically apparent pathology which could progress to blinding stromal keratitis. The genome of the intertypic recombinant was analyzed by agarose gel electrophoresis of restriction endonuclease digests and found to consist entirely of HSV-1 DNA except for HSV-2 DNA sequences located between map units 0.10-0.16, 0.41-0.43, and 0.77-1.0. Potential explanations for the loss of virulence are discussed.


A pseudoepidemic of pulmonary fungal infections related to fiberoptic bronchoscopy.
During a three-week period a pseudoepidemic of fungal infections occurred involving patients from two different services. Trichosporon cutaneum and a Penicillium species were isolated from bronchial washings and sputa obtained after fiberoptic bronchoscopy on eight clinically uninfected patients. Investigation revealed contamination of cocaine solutions used for topical anesthesia during bronchoscopy. Contamination is thought to have occurred during preparation of the solutions by pharmacy personnel. Revision of techniques used in formulating and dispensing the solutions resulted in cessation of the pseudoepidemic.


Etodolac Containing Topical Niosomal Gel: Formulation Development and Evaluation.
The present study aimed to investigate the delivery potential of Etodolac (ETD) containing topical niosomal gel. Niosomal formulations were prepared by thin film hydration method at various ratios of cholesterol and Span 60 and were evaluated with respect to particle size, shape, entrapment efficiency, and in vitro characteristics. Dicetyl phosphate (DCP) was also added in the niosomal formulation. Mean particle size of niosomal formulation was found to be in the range of 2 μm to 4 μm. Niosomal formulation N2 (1 : 1) ratio of cholesterol and surfactant displayed good entrapment efficiency (96.72%). TEM analyses showed that niosomal formulation was spherical in shape. Niosomal formulation (N2) displayed high percentage of drug release after 24 h (94.91) at (1 : 1) ratio of cholesterol : surfactant. Further selected niosomal formulation was used to formulate topical gel and was characterized with respect to its various parameters such as pH, viscosity, spreadability, ex vivo study, and in vivo potential permeation. Ex vivo study showed that niosomal gel possessed better skin permeation study than the plain topical gel. Further in vivo study revealed good inhibition of inflammation in case of topical niosomal gel than plain gel and niosomal formulation. The present study suggested that topical niosomal gel formulations provide sustained and prolonged delivery of drug.


Fast and Specific Screening of EPA/DHA-Enriched Phospholipids in Fish Oil Extracted from Different Species by HILIC-MS.
Eicosapentaenoic acid- and docosahexaenoic acid-enriched phospholipids (PLEPA/DHA) have versatile health-beneficial functions and can be well absorbed in the intestine. Herein, a precursor ion scan-driven hydrophilic interaction chromatography mass spectrometry (PreIS-HILIC-MS) method with the fatty acyl moieties of m/z 301.6 and 327.6 locked was established to specifically and selectively screen PLEPA/DHA in different fish oil samples, including saury, grass carp, hairtail, and yellow croaker. Taking saury oil as an example, a total of 24 PLEPA/DHA were successfully identified and quantified, including 20 PCEPA/DHA and 4 PEEPA/DHA. Finally, this method was validated in terms of sensitivity (limit of detection ≤ 4.15 μg·mL-1), linearity (≥0.9979), precision (RSDintraday ≤ 4.65%), and recovery (≥78.6%). The performance of the PreIS-HILIC-MS method was also compared with that of the traditional full-scan mode, and the former demonstrated its unique superiority in targeted screening of PLEPA/DHA in fish oils.


Maternal nutrient restriction predisposes ventricular remodeling in adult sheep offspring.
Maternal nutrient restriction during pregnancy is associated with the development of a "thrifty phenotype" in offspring, conferring increased prevalence of metabolic diseases in adulthood. To explore the possible mechanisms behind heart diseases in adulthood following maternal nutrient restriction, dams were fed a nutrient-restricted (NR: 50%) or control (100%) diet from 28 to 78 days of gestation. Both groups were then fed 100% of requirements to lambing. At 6 years of age, female offspring of NR and control ewes of similar weight and body condition were subjected to ad libitum feeding of a highly palatable diet for 12 weeks. Cardiac geometry, post-insulin receptor signaling, autophagy and proinflammatory cytokines were evaluated in hearts from adult offspring. Our results indicated that maternal nutrient restriction overtly increased body weight gain and triggered cardiac remodeling in offspring following the 12-week ad libitum feeding. Phosphorylation of insulin receptor substrate-1 (IRS1) was increased in left but not right ventricles from NR offspring. Levels of signal transducer and activator of transcription-3 were up-regulated in left ventricles, whereas expression of tumor necrosis factor-α and toll-like receptor-4 was enhanced in right ventricles, in adult offspring of maternal nutrition-restricted ewes. No significant differences were found in pan-IRS1, pan-AMP-dependent protein kinase (AMPK), pan-Akt, phosphorylated AMPK, phosphorylated Akt, glucose transporter 4, phosphorylated mammalian target of rapamycin, Beclin-1 and microtubule-associated protein 1 light-chain 3 II proteins in left and right ventricles between the control and NR offspring. These data revealed that maternal nutrient restriction during early to mid gestation may predispose adult offspring to cardiac remodeling possibly associated with phosphorylation of IRS1 as well as proinflammatory cytokines but not autophagy.


Microarray analysis of developing flax hypocotyls identifies novel transcripts correlated with specific stages of phloem fibre differentiation.
Hypocotyls are a commonly used model to study primary growth in plants, since post-germinative hypocotyls increase in size by cell elongation rather than cell division. Flax hypocotyls produce phloem fibres in bundles one to two cell layers thick, parallel to the protoxylem poles of the stele. Cell wall deposition within these cells occurs rapidly at a well-defined stage of development. The aim was to identify transcripts associated with distinct stages of hypocotyl and phloem fibre development. Stages of flax hypocotyl development were defined by analysing hypocotyl length in relation to fibre secondary wall deposition. Selected stages of development were used in microarray analyses to identify transcripts involved in the transition from elongation to secondary cell wall deposition in fibres. Expression of specific genes was confirmed by qRT-PCR and by enzymatic assays. Genes enriched in the elongation phase included transcripts related to cell-wall modification or primary-wall deposition. Transcripts specifically enriched at the transition between elongation and secondary wall deposition included beta-galactosidase and arabinogalactan proteins. Later stages of wall development showed an increase in secondary metabolism-related transcripts, chitinases and glycosyl hydrolases including KORRIGAN. Microarray analysis also identified groups of transcription factors enriched at one or more stages of fibre development. Subsequent analysis of a differentially expressed beta-galactosidase confirmed that the post-elongation increase in beta-galactosidase enzyme activity was localized to phloem fibres. Transcripts were identified associated with specific stages of hypocotyl development, in which phloem fibre cells were undergoing thickening of secondary walls. Temporal and spatial regulation of beta-galactosidase activity suggests a role for this enzyme in remodelling of flax bast fibre cell walls during secondary cell wall deposition.


Barrier Functional Integrity Recording on bEnd.3 Vascular Endothelial Cells via Transendothelial Electrical Resistance Detection.
The blood-brain barrier (BBB) is a dynamic physiological structure composed of microvascular endothelial cells, astrocytes, and pericytes. By coordinating the interaction between restricted transit of harmful substances, nutrient absorption, and metabolite clearance in the brain, the BBB is essential in preserving central nervous system homeostasis. Building in vitro models of the BBB is a valuable tool for exploring the pathophysiology of neurological disorders and creating pharmacological treatments. This study describes a procedure for creating an in vitro monolayer BBB cell model by seeding bEnd.3 cells into the upper chamber of a 24-well plate. To assess the integrity of cell barrier function, the conventional epithelial cell voltmeter was used to record the transmembrane electrical resistance of normal cells and CoCl2-induced hypoxic cells in real-time. We anticipate that the above experiments will provide effective ideas for the creation of in vitro models of BBB and drugs to treat disorders of central nervous system diseases.


Sacral neuromodulation in patients with idiopathic overactive bladder after initial botulinum toxin therapy.
We evaluated whether patients with overactive bladder and incontinence who discontinued intravesical botulinum toxin therapy can be successfully treated with sacral neuromodulation. All patients who were referred to our center after discontinuation of botulinum toxin-A between 2005 and 2010 were included in this observational study. All patients underwent test stimulation with sacral neuromodulation and were evaluated with voiding diaries. Success was defined as more than 50% improvement in leakage episodes. Successful test stimulation was subsequently followed by a definitive implant. Patient satisfaction with sacral neuromodulation therapy was evaluated 1 year after the definitive implant. A total of 20 patients were included in the study. Of these patients 17 (85%) had discontinued botulinum toxin-A because of lack of efficacy and 3 had been treated successfully with botulinum toxin-A but requested a more permanent solution. The mean interval between the botulinum toxin-A and the sacral neuromodulation test stimulation was 23 months. In 14 patients (70%) the test stimulation was successful and they received a definitive implant. Of the 14 patients 5 even showed a decrease of greater than 90% in leakage episodes. One year after implantation 11 patients (79%) were satisfied with the sacral neuromodulation treatment. Despite the small sample size, this study indicates that patients who are dissatisfied with or in whom botulinum toxin-A treatment fails can respond successfully to sacral neuromodulation. The success rate of the test stimulation was comparable to that of patients who have never been treated with botulinum toxin-A. The 1-year satisfaction rate was comparable that of patients without a history of botulinum toxin-A treatment.


Intracellular pH homeostasis plays a role in the NaCl tolerance of Debaryomyces hansenii strains.
The effects of NaCl stress on cell area and intracellular pH (pHi) of individual cells of two Debaryomyces hansenii strains were investigated. Our results show that one of the strains was more NaCl tolerant than the other, as determined by the rate of growth initiation. Whereas NaCl stress caused similar cell shrinkages (30-35%), it caused different pHi changes of the two D. hansenii strains; i.e., in the more NaCl-tolerant strain, pHi homeostasis was maintained, whereas in the less NaCl-tolerant strain, intracellular acidification occurred. Thus, cell shrinkage could not explain the different intracellular acidifications in the two strains. Instead, we introduce the concept of yeasts having an intracellular pKa (pK(a,i)) value, since permeabilized D. hansenii cells had a very high buffer capacity at a certain pH. Our results demonstrate that the more NaCl-tolerant strain was better able to maintain its pK(a,i) close to its pHi homeostasis level during NaCl stress. In turn, these findings indicate that the closer a D. hansenii strain can keep its pK(a,i) to its pHi homeostasis level, the better it may manage NaCl stress. Furthermore, our results suggest that the NaCl-induced effects on pHi were mainly due to hyperosmotic stress and not ionic stress.


Are the asthma guideline goals achieved in daily practice? A population-based study on treatment adequacy and the control of asthma.
The guidelines for asthma recommend that the use of anti-inflammatory therapy should be adapted to the severity of the disease. However, few data are available to assess the adequacy of the use of drugs and its influence on the control of asthma in 'real life'. The adequacy of the current use of anti-asthmatic medication according to the Global Initiative for Asthma (GINA) guidelines was assessed in a random sample of 400 asthmatics identified in the frame of the Italian Study on Asthma in Young Adults. Asthma severity was assessed using the GINA criteria; accordingly, a patient was classified as receiving inadequate treatment if his/her current use of drugs was lower than that suggested by the guidelines for the corresponding severity level. The absence of asthma attacks in the last 3 months was used as an indicator of the disease control. Fifty-five percent of the patients had persistent asthma. Overall, 48% (95% CI 41.2-54.8) of persistent asthmatics were receiving inadequate treatment, and 66% (95% CI 59.5-72.4) had not used their medication daily over the past 3 months. Persistent asthmatics who were inadequately treated had a significantly greater frequency of asthma attacks (geometric mean ratio 3.7; 95% CI 2.1-6.6) than those using an adequate dose of medication. Mild and moderate persistent asthmatics using an adequate medication regimen reported a low number of asthma attacks (median 0). At the multivariate analysis, a good control of the disease was positively associated with an adequate dose of anti-inflammatory medication (OR = 2.2; 95% CI 1.1-4.5) and was negatively associated with a later onset of asthma (OR = 0.96; 95% CI 0.93-0.99) and severe asthma (OR = 0.37; 95% CI 0.17-0.81). Despite the increase in the use of inhaled corticosteroids, half of the persistent asthmatics from the general population are using a medication regimen below their severity level. When the use of drugs follows the GINA guideline recommendations, a good control of asthma is also achievable in the daily management of the disease, particularly in the case of mild and moderate asthmatics.


Dalbavancin (Biosearch Italia/Versicor).
Biosearch Italia and Versicor are developing dalbavancin, a novel semisynthetic derivative of the natural glycopeptide A-40926 for the potential treatment of Gram-positive infections. In May 2001, the compound entered phase II trials in the US [409929], [409932]. As of Janaury 2002, phase II trials in skin infections and bacteremia were ongoing [436430]. Both dalbavancin and MDL-63246 are dimethylaminopropyl amide derivatives of A-40926; dalbavancin differs from MDL-63246 in its acylamino sugar, which consists of glucuronic acid in dalbavancin and glucosamine in MDL-63246 [216093], [298527]. The development of MDL-63246 has been discontinued [298527]. In January 1999, Versicor gained North American market rights to BI-397 [311500]. In January 2002, UBS Warburg predicted filing of an NDA in the second half of 2003 for dalbavancin, for treatment of complicated skin and soft tissue infections [439472]. In December 2001, Lehman Brothers predicted a late 2005 launch for dalbavancin, with sales of US $7.7 million in 2005, US $65.8 million in 2006, and peak sales of US $225 million in 2008 [439469].


Repeated measurements of mite and pet allergen levels in house dust over a time period of 8 years.
Studies of the association between indoor allergen exposure and the development of allergic diseases have often measured allergen exposure at one point in time. We investigated the variability of house dust mite (Der p 1, Der f 1) and cat (Fel d 1) allergen in Dutch homes over a period of 8 years. Data were obtained in the Dutch PIAMA birth cohort study. Dust from the child's mattress, the parents' mattress and the living room floor was collected at four points in time, when the child was 3 months, 4, 6 and 8 years old. Dust samples were analysed for Der p 1, Der f 1 and Fel d 1 by sandwich enzyme immuno assay. Mite allergen concentrations for the child's mattress, the parents' mattress and the living room floor were moderately correlated between time-points. Agreement was better for cat allergen. For Der p 1 and Der f 1 on the child's mattress, the within-home variance was close to or smaller than the between-home variance in most cases. For Fel d 1, the within-home variance was almost always smaller than the between-home variance. Results were similar for allergen levels expressed per gram of dust and allergen levels expressed per square metre of the sampled surface. Variance ratios were smaller when samples were taken at shorter time intervals than at longer time intervals. Over a period of 4 years, mite and cat allergens measured in house dust are sufficiently stable to use single measurements with confidence in epidemiological studies. The within-home variance was larger when samples were taken 8 years apart so that over such long periods, repetition of sampling is recommended.


Apoptosis and in situ and invasive squamous cell carcinoma in sun-exposed sites.
In vitro evidence indicates that the E6 protein of human papillomavirus (HPV) targets Bak, a proapoptotic protein, expression of which is enhanced in epidermal keratinocytes in response to ultraviolet B radiation. Given this, our aim was to ascertain Bak expression and prevalence of beta-HPV (β-HPV) in cutaneous squamous cell carcinoma (SCC) from sun-exposed sites to test our hypothesis that the virus plays a role in the neoplastic process by suppressing UV-induced apoptosis. This retrospective study included 30 cases of cutaneous SCC and 30 cases of SCC in situ (SCCIS) from sun-exposed sites. Immunohistochemical staining for Bak protein was performed on all, and β-HPV subtyping on 10 randomly selected cases from each group, using a broad-spectrum polymerase chain reaction-reverse hybridization assay. A semiquantitative scoring system for immunohistochemical expression of Bak was used based on the percentage positivity of the cells. Of cases studied, 30 of 30 (100%) of SCCIS and SCC (mean score 4.2 and 4.6, respectively, demonstrated immunopositivity, albeit to varying degrees, with Bak. Of the selected cases studied with reverse hybridization assay, 7 of 10 (70%) of SCCIS and 3 of 10 (30%) of SCC had β-HPV with HPV-5 being the most common subtype detected. Enhanced Bak immunoexpression confirms the presence of UV-induced apoptosis in both in situ as well as invasive epithelial malignancies, although the lack of differences in expression of Bak between both groups studied suggests that its relevance in disease progression is minimal. Expression of Bak in 100% of HPV-containing lesions from sun-exposed sites suggests that the virus does not abrogate UV-induced apoptosis.


[Inappropriate combinations of antiretroviral drugs].
At present 19 antiretroviral drugs are available, which offer together 969 possible triple-combinations. Only a few combinations, mainly of nucleoside inhibitors of reverse transcriptase, are contraindicated due to undesirable interactions, which may negatively influence the treatment efficacy or increase toxicity. With raising number of antiretroviral drugs there must also be paid more attention to possible interactions of these drugs.


Family breakup and adolescents' psychosocial maladjustment: public health implications of family disruptions.
Recent changes in family structure are associated with an increase in psychosocial maladjustment in adolescents. We examined, from a public health intervention perspective, the association between family breakup and psychosocial maladjustment in adolescents and assessed the mediating role of family-functioning variables. We analyzed data from the Social and Health Survey of Children and Adolescents in Quebec, Montreal, Canada, which was conducted in 1999. Sample-weighted logistic regression analyses were performed to determine the risk of internalizing disorders, externalizing disorders, substance abuse, and alcohol consumption in relation to family breakups and family-functioning variables, after adjusting for socioeconomic factors. All 4 of the indicators of psychosocial maladjustment were significantly associated with family breakup. The association between family breakups and internalizing disorders was mediated by parental psychological distress and low paternal emotional support. Independently, the witnessing of interparental violence was also strongly associated with internalizing disorders. For the other 3 outcomes, that is, externalizing disorders, substance abuse, and alcohol consumption, family breakup and family-functioning variables had independent effects. Family-based interventions and social approaches are complementary support modalities for adolescents experiencing family disruptions.


Influence of the stage of advancement of leukemia L1210 in mice on the optimal schedule of treatment of cytosine arabinoside (NSC-63878).
Treatment with cytosine arabinoside given intraperitoneally (ip) every 3 hours for 24 hours on every fourth day (Q3h/24h/4d) from 1 day after ip implantation of 10(6) or 10(7) leukemia L1210 cells in mice, was not observed to be superior to the same treatment after implantation of 10(5) cells. Similarly, when cytosine arabinoside therapy was delayed until Day 5 after 10(5) tumor cells were implanted, treatment Q3h/24h/4d did not provide a therapeutic advantage over treatment with a single injection every second or fourth day. A single treatment of the advanced disease with cyclophosphamide did not restore the sensitivity of the disease to the Q3h/24h/4d treatment schedule. Whether treatment with cytosine arabinoside was started on Days 1, 3, or 5, the optimal total dose per day for treatment given once every fourth day was 12-20 times greater than the optimal total dose per day for treatment given in eight equal injections every fourth day. Via the oral route, the Q3h/24h/4d treatment regimen was not superior to one treatment every fourth day from Day 1. The data clearly show that when the initial inoculum is high (10(6) or 10(7) cells) or when the disease is advanced, the response to cytosine arabinoside therapy does not display treatment-schedule dependency for the Q3h/24h/4d schedule.


Functional properties and molecular structure of central and peripheral neurotensin receptors.
Membranes prepared from mammalian brain or intestine contain two types of specific binding sites for neurotensin that differ by their affinity and by their sensitivity to sodium ions, GTP, and the antihistamine drug levocabastine. Only the high affinity sites are present in cell cultures and in soluble extracts of CHAPS-treated membranes. These sites represent functional neurotensin receptors coupled to GTP-binding proteins that regulate intracellular levels of cAMP, cGMP and inositol phosphates in neuroblastoma N1E115 cells. The molecular weight of neurotensin receptors in cells and membrane preparations of various origin is about 110,000.


Intraoperative Assessment of DIEP Flap Breast Reconstruction Using Indocyanine Green Angiography: Reduction of Fat Necrosis, Resection Volumes, and Postoperative Surveillance.
This study aims to characterize the effect of laser-assisted indocyanine green fluorescence angiography on fat necrosis and flap failure in deep inferior epigastric artery perforator (DIEP) flap breast reconstruction. A retrospective review was performed on 1000 free flaps for breast reconstruction at a single center from 2010 to 2017. Indocyanine green angiography was used after completion of recipient-site anastomoses to subjectively assess for areas of hypoperfusion. A multivariable logistical analysis was conducted with 24 demographic and surgical factors and their effects on fat necrosis and flap failure. Five hundred six DIEP flaps were included in the statistical analyses. Thirteen percent of flaps had fat necrosis. Indocyanine green angiography was used for 200 flaps and was independently associated with a decrease in the odds of fat necrosis (OR, 0.38; p = 0.004). There was no reduction in flap failure rates when using indocyanine green angiography (OR, 1.15; p = 0.85). However, there was a decrease in flap loss with increasing venous coupler diameter (OR, 0.031 per 1-mm increase; p = 0.012). The 84.9-g higher weight of resected tissue before inset without indocyanine green angiography versus the weight of the tissue resected with indocyanine green angiography was statistically significant (p = 0.01). Per single incident of fat necrosis, our cohort underwent an additional 0.69 revision procedures, 1.22 imaging studies, 0.77 biopsies, and 1.7 additional oncologic office visits. Intraoperative indocyanine green fluorescence angiography decreases the odds of fat necrosis, saves volume when flap trimming at inset, and can significantly reduce the postoperative surveillance burden in DIEP-based breast reconstruction. Therapeutic, III.


Salinity Treatments Promote the Accumulations of Momilactones and Phenolic Compounds in Germinated Brown Rice.
This is the first investigation, conducted in a completely randomized design (CRD), to determine the effects of different salinity levels (75 and 150 mM) and germination periods (3, 4, and 5 days) on momilactone and phenolic accumulations in germinated brown rice (GBR) var. Koshihikari. Particularly, the identification of bioactive compounds was confirmed using electrospray ionization-mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR) spectroscopy (1H and 13C). Momilactone A (MA) and momilactone B (MB) amounts were determined by ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS), whereas other compounds were quantified by spectrophotometry and high-performance liquid chromatography (HPLC). Accordingly, GBR under B2 treatment (75 mM salinity for 4 days) showed the greatest total phenolic and flavonoid contents (14.50 mg gallic acid and 11.06 mg rutin equivalents, respectively, per g dry weight). GBR treated with B2 also accumulated the highest quantities of MA, MB, ρ-coumaric, ferulic, cinnamic, salicylic acids, and tricin (18.94, 41.00, 93.77, 139.03, 46.05, 596.26, and 107.63 µg/g DW, respectively), which were consistent with the strongest antiradical activities in DPPH and ABTS assays (IC50 = 1.58 and 1.78 mg/mL, respectively). These findings have implications for promoting the value of GBR consumption and rice-based products that benefit human health.


"They're just, like, there": A constructivist grounded theory study of student experiences with school resource officers.
School-based policing has become common practice, but there is limited qualitative research examining what meanings students make of police presence in their schools. This study sought to understand how students construct narratives of police presence in their schools based on their experiences with school resource officers (SROs). Drawing on constructivist grounded theory methodology with a sample of 17 students, this study found that students are continuously integrating multiple conflicting narratives about SROs: students experience SROs as an established yet ambiguous presence, which produces mixed feelings of reassurance, wariness, and intimidation. Students manage the conflicts between these narratives by positioning school-based police as a fixed structure with pitfalls and positives but no alternatives. Additionally, students experience SROs as being available to them in relational capacities. The primary recommendations from this study are for schools and communities to (1) reconsider the appropriateness of SRO programs with student perspectives at the center of dialogue, and (2) invest in non-law enforcement school-based professionals who students experience as available and relational.


[A Case of Isolated Peritoneal Metastasis from Prostate Cancer].
Peritoneal metastasis of prostate cancer is extremely rare, with only a few cases reported. A 78-yearold male patient was introduced to our hospital presenting with a prostate-specific antigen (PSA) level of 94.0 ng/ml at examination. He was diagnosed with poorly differentiated adenocarcinoma of the prostate, with a Gleasonscore of 9 (5+4) at cT3bN0M0. Intensity-modulated radiation therapy was performed after 6 months of combined-androgen blockade (CAB) therapy. Twenty-one months later, several lymph node metastases were observed. With the resumptionof CAB therapy, PSA levels dropped and the multiple lymph node metastasis disappeared ; however, peritoneal metastasis was observed after 43 months. We performed a laparoscopic biopsy and our diagnosis after pathological evaluation was metastasis of the prostate cancer. He was treated with Enzalutamide.


Evaluation of a mixture of zinc oxide, calcium hydroxide, and sodium fluoride as a new root canal filling material for primary teeth.
Endodontic treatment was performed on 25 pulpally involved mandibular primary molars in 4 to 9-year-old children; the root canals were obturated with a new root canal filling material consisting of a mixture of calcium hydroxide, zinc oxide, and 10% sodium fluoride solution, using hand-operated lentulo-spirals. All cases were evaluated clinically every 3 months and also radiographically every 6 months to assess the success of the treatment; we also examined the resorption of the root canal filling material from the root canals and the status of overpushed material, if any, as the tooth resorbed with the passage of time. At 6 months, endodontic treatment in 2 of the 25 teeth had failed and one tooth had exfoliated; the remaining 22 teeth were without any signs or symptoms. At the end of 2 years, 14 teeth could be evaluated; out of these 12 had physiologically exfoliated. It was observed that the rate of resorption of this new root canal obturating mixture was quite similar to the rate of physiologic root resorption in primary teeth. In three cases, where there was an overpush of the mixture, a gradual partial resorption was noted.


Purification and characterization of a human erythrocyte-derived growth factor with a wide target cell spectrum.
A cell extract from human erythrocytes promoted the growth of a wide variety of cell types, namely human and mouse myeloid cells, human and mouse T cells, human B cells, human melanoma cells, mouse transformed fibroblast cells, mouse mastocytoma cells, human lung fibroblast cells, and mouse bone marrow fibroblast/stroma-like cells. The growth-promoting activity was acid- and heat-labile and sensitive to proteases, indicating the proteinaceous nature of the molecule. The activity was also lost upon exposure to 2-mercaptoethanol. The novel growth-promoting factor, termed basic growth factor because of its fundamental effect and a wide target cell spectrum, was purified by sequential anion-exchange, hydrophobic, gel filtration, hydroxylapatite, and reverse-phase high performance liquid chromatographies. The purified factor has an apparent molecular mass of 53 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing and nonreducing conditions. The factor migrated at 270 kDa on native gradient polyacrylamide gel electrophoresis. Therefore, the factor consists of a homopolymer of a single polypeptide chain. The purified factor promoted the growth of the same cell types as the cell extract, except for bone marrow cells.


Cognitive endpoints as disease biomarkers: optimizing the congruency of preclinical models to the clinic.
Cognition is a complex set of processes, including attention, learning and memory, that refers to the capacity to encode, consolidate, store and retrieve recent and remotely stored fact (semantic) and experience-based (episodic) memory. The development of cognitive enhancers is of particular importance to society and the pharmaceutical industry, as cognitive dysfunctions are observed across a wide range of neuropsychiatric and neurodegenerative disorders; however, developing such therapeutics has proven difficult. There is poor congruency between the abundance of positive results observed in animal studies compared with clinical outcome. For example, from 1982 to 2002 there was a 6000% increase in studies on cognitive processing in rodents that had little or no impact on the outcome of phase II and III clinical trials. The effects of therapeutics on models of cognition that demonstrate the potential to improve preclinical-to-clinical congruency, focusing on attention, impulsivity and episodic memory, are summarized in this review. Changes in attention, impulsivity and episodic memory are tractable 'disease biomarkers' that correlate with the disease phenotypes that are potential therapeutic targets. In the context of the development of cognitive enhancing drugs, one of the major goals of translational medicine is to improve the congruency between preclinical models and clinical results. Improved translatability could improve discovery, validation and implementation of biomarkers to inform clinical outcome studies and decision making, and to establish proof-of-concept for efficacy and safety based on targeted mechanisms of action.


Medicare Program; Prospective Payment System and Consolidated Billing for Skilled Nursing Facilities (SNF) Final Rule for FY 2019, SNF Value-Based Purchasing Program, and SNF Quality Reporting Program. Final rule.
This final rule updates the payment rates used under the prospective payment system (PPS) for skilled nursing facilities (SNFs) for fiscal year (FY) 2019. This final rule also replaces the existing case-mix classification methodology, the Resource Utilization Groups, Version IV (RUG–IV) model, with a revised case-mix methodology called the Patient- Driven Payment Model (PDPM) beginning on October 1, 2019. The rule finalizes revisions to the regulation text that describes a beneficiary's SNF "resident" status under the consolidated billing provision and the required content of the SNF level of care certification. The rule also finalizes updates to the SNF Quality Reporting Program (QRP) and the Skilled Nursing Facility Value-Based Purchasing (VBP) Program.


Selective upregulation of scavenger receptors in and around demyelinating areas in multiple sclerosis.
Autoantibodies and complement opsonization have been implicated in the process of demyelination in the major human CNS demyelinating disease multiple sclerosis (MS), but scavenger receptors (SRs) may also play pathogenetic roles. We characterized SR mRNA and protein expression in postmortem brain tissue from 13 MS patients in relation to active demyelination. CD68, chemokine (C-X-C motif) ligand 16 (CXCL16), class A macrophage SR (SR-AI/II), LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1), FcγRIII, and LRP-1 (low-density lipoprotein receptor-related protein 1) mRNA were upregulated in the rims of chronic active MS lesions. CD68 and CXCL16 mRNA were also upregulated around chronic active MS lesions. By immunohistochemistry, CD68, CXCL16, and SR-AI/II were expressed by foamy macrophages in the rim and by ramified microglia around chronic active MS lesions. CXCL16 and SR-AI/II were also expressed by astrocytes in MS lesions and by primary human microglia and astrocytes in vitro. These data suggest that SRs are involved in myelin uptake in MS, and that upregulation of CD68, CXCL16, and SR-AI/II is one of the initial events in microglia as they initiate myelin phagocytosis. As demyelination continues, additional upregulation of LOX-1, FcγRIII, and LRP-1 may facilitate this process.


Mushroom-Derived Indole Alkaloids.
Mushrooms are known to produce over 140 natural products bearing an indole heterocycle. In this review, the isolation of these mushroom-derived indole alkaloids is discussed, along with their associated biological activities.


[Effect of polycystin2 on differentiation and maturation of osteoblasts promoted by low-frequency pulsed electromagnetic fields].
It is known that low-frequency pulsed electromagnetic fields (PEMFs) can promote the differentiation and maturation of rat calvarial osteoblasts (ROBs) cultured in vitro. However, the mechanism that how ROBs perceive the physical signals of PEMFs and initiate osteogenic differentiation remains unknown. In this study, we investigated the relationship between the promotion of osteogenic differentiation of ROBs by 0.6 mT 50 Hz PEMFs and the presence of polycystin2 (PC2) located on the primary cilia on the surface of ROBs. First, immunofluorescence staining was used to study whether PC2 is located in the primary cilia of ROBs, and then the changes of PC2 protein expression in ROBs upon treatment with PEMFs for different time were detected by Western blotting. Subsequently, we detected the expression of PC2 protein by Western blotting and the effect of PEMFs on the activity of alkaline phosphatase (ALP), as well as the expression of Runx-2, Bmp-2, Col-1 and Osx proteins and genes related to bone formation after pretreating ROBs with amiloride HCl (AMI), a PC2 blocker. Moreover, we detected the expression of genes related to bone formation after inhibiting the expression of PC2 in ROBs using RNA interference. The results showed that PC2 was localized on the primary cilia of ROBs, and PEMFs treatment increased the expression of PC2 protein. When PC2 was blocked by AMI, PEMFs could no longer increase PC2 protein expression and ALP activity, and the promotion effect of PEMFs on osteogenic related protein and gene expression was also offset. After inhibiting the expression of PC2 using RNA interference, PEMFs can no longer increase the expression of genes related to bone formation. The results showed that PC2, located on the surface of primary cilia of osteoblasts, plays an indispensable role in perceiving and transmitting the physical signals from PEMFs, and the promotion of osteogenic differentiation of ROBs by PEMFs depends on the existence of PC2. This study may help to elucidate the mechanism underlying the promotion of bone formation and osteoporosis treatment in low-frequency PEMFs.


The Impact of Bacterial Biofilms on End-Organ Disease and Mortality in Patients with Hematologic Malignancies Developing a Bloodstream Infection.
Bacterial bloodstream infection (BSI) represents a significant complication in hematologic patients. However, factors leading to BSI and progression to end-organ disease and death are understood only partially. The study analyzes host and microbial risk factors and assesses their impact on BSI development and mortality. A total of 96 patients with hematological malignancies and BSI were included in the study. Host-associated risk factors and all causes of mortality were analyzed by multivariable logistic regression at 30 days after BSI onset of the first neutropenic episode. The multidrug-resistant profile and biofilm production of bacterial isolates from primary BSI were included in the analysis. Median age was 60 years. The underlying diagnoses were acute leukemia (55%), lymphoma (31%), and myeloma (14%). A total of 96 bacterial isolates were isolated from BSIs. Escherichia coli was the most common isolate (29.2%). Multidrug-resistant bacteria caused 10.4% of bacteremia episodes. Weak biofilm producers (WBPs) were significantly (P < 0.0001) more abundant (72.2%) than strong biofilm producers (SBPs) (27.8%). Specifically, SBPs were 7.1% for E. coli, 93.7% for P. aeruginosa, 50% for K. pneumoniae, and 3.8% for coagulase-negative staphylococci. Mortality at day 30 was 8.3%, and all deaths were attributable to Gram-negative bacteria. About 22% of all BSIs were catheter-related BSIs (CRBSIs) and mostly caused by Gram-positive bacteria (79.0%). However, CRBSIs were not correlated with biofilm production levels (P = 0.75) and did not significantly impact the mortality rate (P = 0.62). Conversely, SBP bacteria were an independent risk factor (P = 0.018) for developing an end-organ disease. In addition, multivariate analysis indicated that SBPs (P = 0.013) and multidrug-resistant bacteria (P = 0.006) were independent risk factors associated with 30-day mortality. SBP and multidrug-resistant (MDR) bacteria caused a limited fraction of BSI in these patients. However, when present, SBPs raise the risk of end-organ disease and, together with an MDR phenotype, can independently and significantly concur at increasing the risk of death. IMPORTANCE Bacterial bloodstream infection (BSI) is a significant complication in hematologic patients and is associated with high mortality rates. Despite improvements in BSI management, factors leading to sepsis are understood only partially. This study analyzes the contribution of bacterial biofilm on BSI development and mortality in patients with hematological malignancies (HMs). In this work, weak biofilm producers (WBPs) were significantly more abundant than strong biofilm producers (SBPs). However, when present, SBP bacteria raised the risk of end-organ disease in HM patients developing a BSI. Besides, SBPs, together with a multidrug-resistant (MDR) phenotype, independently and significantly concur at increasing the risk of death in HM patients. The characterization of microbial biofilms may provide key information for the diagnosis and therapeutic management of BSI and may help develop novel strategies to either eradicate or control harmful microbial biofilms.


Learning via instructions about observations: exploring similarities and differences with learning via actual observations.
Our behaviour toward stimuli can be influenced by observing how another person (a model) interacts with those stimuli. We investigated whether mere instructions about a model's interactions with stimuli (i.e. instructions about observations) are sufficient to alter evaluative and fear responses and whether these changes are similar in magnitude to those resulting from actually observing the interactions. In Experiments 1 (n = 268) and 2 (n = 260), participants either observed or read about a model reacting positively or negatively to stimuli. Evaluations of those stimuli were then assessed via ratings and a personalized implicit association test. In Experiments 3 (n = 60) and 4 (n = 190), we assessed participants' fear toward stimuli after observing or reading about a model displaying distress in the presence of those stimuli. While the results consistently indicated that instructions about observations induced behavioural changes, they were mixed with regard to whether instructions were as powerful in changing behaviour as observations. We discuss whether learning via observations and via instructions may be mediated by similar or different processes, how they might differ in their suitability for conveying certain types of information, and how their relative effectiveness may depend on the information to be transmitted.


Cathepsin K: The Action in and Beyond Bone.
Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.


MicroRNA-let-7e regulates the progression and development of allergic rhinitis by targeting suppressor of cytokine signaling 4 and activating Janus kinase 1/signal transducer and activator of transcription 3 pathway.
The present study aimed to explore the microRNA-let-7e (miR-let-7e) expression in allergic rhinitis (AR), and to investigate the underlying molecular mechanisms. miR-let-7e expression in the nasal mucosa of mice and patients with AR were detected. The expression levels of three inflammatory factors, including histamine, immunoglobulin E and tumor necrosis factor-α (TNF-α), in the blood of AR mice and in interleukin (IL)-13-stimulated nasal epithelial cells (NECs) were also measured. Furthermore, the target gene of miR-let-7e was predicted and validated using a luciferase reporter assay. The expression levels of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) were detected. The results demonstrated that miR-let-7e was downregulated in patients and mice with AR compared with the controls. In addition, the expression levels of inflammatory factors were higher in the blood of mice with AR compared with the control group, while miR-let-7e overexpression inhibited these levels in AR mice and IL-13-stimulated NECs. Furthermore, suppressor of cytokine signaling 4 (SOCS4) was revealed as a potential target gene of miR-let-7e and was negatively regulated by miR-let-7e. Overexpression of SOCS4 abrogated the anti-inflammatory activity of miR-let-7e overexpression. Finally, miR-let-7e overexpression activated the JAK1/STAT3 signaling pathway. In conclusion, miR-let-7e may serve an important role in the progression and development of AR, while overexpression of miR-let-7e had an anti-inflammatory effect by targeting SOCS4, which may be achieved by activation of the JAK1/STAT3 signaling pathway.


Microbial reprogramming inhibits Western diet-associated obesity.
A recent epidemiological study showed that eating 'fast food' items such as potato chips increased likelihood of obesity, whereas eating yogurt prevented age-associated weight gain in humans. It was demonstrated previously in animal models of obesity that the immune system plays a critical role in this process. Here we examined human subjects and mouse models consuming Westernized 'fast food' diet, and found CD4(+) T helper (Th)17-biased immunity and changes in microbial communities and abdominal fat with obesity after eating the Western chow. In striking contrast, eating probiotic yogurt together with Western chow inhibited age-associated weight gain. We went on to test whether a bacteria found in yogurt may serve to lessen fat pathology by using purified Lactobacillus reuteri ATCC 6475 in drinking water. Surprisingly, we discovered that oral L. reuteri therapy alone was sufficient to change the pro-inflammatory immune cell profile and prevent abdominal fat pathology and age-associated weight gain in mice regardless of their baseline diet. These beneficial microbe effects were transferable into naïve recipient animals by purified CD4(+) T cells alone. Specifically, bacterial effects depended upon active immune tolerance by induction of Foxp3(+) regulatory T cells (Treg) and interleukin (Il)-10, without significantly changing the gut microbial ecology or reducing ad libitum caloric intake. Our finding that microbial targeting restored CD4(+) T cell balance and yielded significantly leaner animals regardless of their dietary 'fast food' indiscretions suggests population-based approaches for weight management and enhancing public health in industrialized societies.


Auditory magnetic responses of healthy newborns.
We recorded magnetic brain activity from healthy human newborns when they heard frequency changes in an otherwise repetitive sound stream. We were able to record the magnetic counterpart of the mismatch negativity (MMN) previously described only with electric recordings in infants. The results show that these recordings are possible, although still challenging due to the small head size and head movements. The modelling of the neural sources underlying the recorded responses suggests cortical sources in the temporal lobes.


MLVA typing of Mycoplasma hyopneumoniae bacterins and field strains.
Because of the lack of information about both the genetic characteristics of Mycoplasma hyopneumoniae commercial vaccines and their relationship with field strains, the authors attempted to identify genetic subtypes of some M hyopneumoniae bacterins, and to compare them with M. hyopneumoniae field strains. Six commercial M hyopneumoniae bacterins and 28 bronchoalveolar lavages from pigs at slaughter from three herds were analysed by Multiple-Locus Variable number tandem repeat Analysis (MLVA) on p146R1, p146R3, H4, H5 and p95 loci. The results obtained showed the presence of more than one M hyopneumoniae genotype in some pigs and also in one of the bacterins analysed. It is also worth noting that MLVA typing allowed the distinction among circulating field strains and also when comparing them with vaccine strains, which, knowing the relatedness among them, could be useful in the research of the efficacy of the vaccines.


Synthesis of N-Acylsulfenamides from Amides and N-Thiosuccinimides.
Herein is reported a robust and general method for the preparation of N-acylsulfenamides, important functionalities that have recently been utilized as central inputs for the asymmetric synthesis of high oxidation state sulfur compounds. This straightforward transformation proceeds by reaction of primary amides, carbamates, sulfonamides, sulfinamides, and ureas with stable N-thiosuccinimides or N-thiophthalimides, which in turn are prepared in a single step from commercial thiols. The use of stable N-thiosuccinimide and N-thiophthalimide reactants is desirable because it obviates the use of highly reactive sulfenyl chlorides.


Cholangiocarcinoma in Cirrhosis: Value of Hepatocyte Specific Magnetic Resonance Imaging.
The diagnosis of intrahepatic cholangiocellular carcinoma (ICC) remains elusive at imaging, which is a critical issue in cirrhotic patients in whom a diagnosis of hepatocellular carcinoma (HCC) can be established only by imaging. The aim of the study was to evaluate the potential of MRI in the diagnosis of ICC in cirrhosis using 'hepatocyte-specific' Gadolinium (Gd)-based contrast agents. Sixteen histologically proven and retrospectively identified ICCs on cirrhosis were investigated with hepatocyte-specific magnetic resonance contrast agents (6 in Bologna with Gd-EOB-DTPA and 10 in Milan with Gd-BOPTA). The control group consisted of 41 consecutively and prospectively collected nodules (31 HCCs) imaged with Gd-EOB-DTPA. Fifteen ICC nodules (94%) displayed hypointensity in the hepatobiliary phase, suggesting malignancy. Thirteen cholangiocarcinomas (81%) showed hyperenhancement in the venous phase. Only 2 cholangiocarcinoma nodules showed hypoenhancement in the venous phase, corresponding to washout, in both cases preceded by rim enhancement in arterial phase. All the hepatocarcinomas showed hypointensity in hepatobiliary phase, but was always preceded by hypointensity in the venous phase; arterial rim enhancement was never observed in any hepatocarcinoma or regenerative nodule. MRI with hepatocyte-specific Gd-based contrast agents showed a pattern of malignancy in almost all the ICCs, concurrently avoiding misdiagnosis with hepatocarcinoma. These findings suggest a greater diagnostic capacity for this technique compared with the results of MRI with conventional contrast agents reported in the literature in this setting.


Update on pathogenesis, management, and treatment of hypertension in autosomal dominant polycystic kidney disease.
Hypertension is a common early finding in autosomal dominant polycystic kidney disease (ADPKD). Improvements in screening and diagnosis of ADPKD have allowed earlier diagnosis, later onset of end-stage renal disease, and better survival. However, the main and most effective therapy remains control of hypertension. Hypertension is the most important modifiable risk factor in ADPKD. Therefore, early management of hypertension reduces the incidence of cardiovascular events in ADPKD patients. Stimulation of the renin-angiotensin-aldosterone system (RAAS) plays a central role in the pathogenesis of hypertension in ADPKD. Therapies that block the RAAS have improved patient management, blood pressure control, and ADPKD patient survival. This review highlights the current understanding of the epidemiology, potential pathogenetic mechanisms and proposes a strategy for the treatment and management of hypertension in ADPKD.


Triangular tessellation scheme for the adsorption free energy at the liquid-liquid interface: Towards nonconvex patterned colloids.
We present a numerical technique, namely, triangular tessellation, to calculate the free energy associated with the adsorption of a colloidal particle at a flat interface. The theory and numerical scheme presented here are sufficiently general to handle nonconvex patchy colloids with arbitrary surface patterns characterized by a wetting angle, e.g., amphiphilicity. We ignore interfacial deformation due to capillary, electrostatic, or gravitational forces, but the method can be extended to take such effects into account. It is verified that the numerical method presented is accurate and sufficiently stable to be applied to more general situations than presented in this paper. The merits of the tessellation method prove to outweigh those of traditionally used semianalytic approaches, especially when it comes to generality and applicability.


Polatuzumab Vedotin Approved for DLBCL.
The antibody-drug conjugate polatuzumab vedotin has been approved to treat relapsed or refractory diffuse large B-cell lymphoma. The drug recognizes the CD79b protein on B cells and kills them with a molecule that prevents tubulin polymerization.


Processing of in vitro-synthesized gag precursor proteins of human immunodeficiency virus (HIV) type 1 by HIV proteinase generated in Escherichia coli.
We expressed the gag and proteinase regions of human immunodeficiency virus (HIV) type 1 by transcription and translation in vitro. A synthetic RNA spanning the gag and pro domains gave primarily the unprocessed capsid precursor pr53. Efficient cleavage of this precursor was observed when the gag and pro domains were placed in the same translational reading frame, yielding equimolar amounts of the gag protein and of proteinase (PR). Expression of HIV type 1 PR in Escherichia coli as a fusion protein gave rapid autocatalytic processing to an HIV-specific protein of approximately 11 kilodaltons. HIV PR generated in E. coli specifically induced cleavage of the HIV capsid precursor, whereas deletion of the carboxy-terminal 17 amino acids of the proteinase rendered it inactive. Inhibitor studies showed that the enzyme was insensitive to inhibitors of serine and cysteine proteinases and metalloproteinases and was inhibited only by a very high concentration (1 mM) of pepstatin A.


Construction of a three-dimensional urothelium on-chip with barrier function based on urinary flow microenvironment.
The urothelium covers the inner surface of the urinary tract, forming a urinary tract barrier. Impairment of the integrity and dysfunction of the urinary tract barrier is associated with the occurrence and development of various diseases. The development of a three-dimensional model of the urothelium is critical for pathophysiological studies of this site, especially under physiological fluid shear stress stimulated by the urinary flow. In this study, a urothelium on-chip is fabricated with micromilling and replica molding techniques, which contains a microfluidic chip for cell culture and a pump-based fluid perfusion system. The mechanical properties of the human urinary tract are simulated by adjusting the concentration and degree of amino substitution of the gelatin methacrylate hydrogel. The matrix stiffness is similar to the natural urinary tract. Pulsatile flow and periodic flow are provided to simulate the fluid environment of the upper and lower urinary tracts, respectively. The results show that the physiological fluid shear stress could promote the differentiation and maturation of urothelial cells. The model could simulate the three-dimensional structure of urothelium and urinary flow microenvironment, showing morphological structure close to the natural urothelium, specific differentiation and maturation markers (uroplakin 2, cytokeratin 20), and urothelial barrier function.


Gut microbiome signatures of Yorkshire Terrier enteropathy during disease and remission.
The role of the gut microbiome in developing Inflammatory Bowel Disease (IBD) in humans and dogs has received attention in recent years. Evidence suggests that IBD is associated with alterations in gut microbial composition, but further research is needed in veterinary medicine. The impact of IBD treatment on the gut microbiome needs to be better understood, especially in a breed-specific form of IBD in Yorkshire Terriers known as Yorkshire Terrier Enteropathy (YTE). This study aimed to investigate the difference in gut microbiome composition between YTE dogs during disease and remission and healthy Yorkshire Terriers. Our results showed a significant increase in specific taxa such as Clostridium sensu stricto 1, Escherichia-Shigella, and Streptococcus, and a decrease in Bacteroides, Prevotella, Alloprevotella, and Phascolarctobacterium in YTE dogs compared to healthy controls. No significant difference was found between the microbiome of dogs in remission and those with active disease, suggesting that the gut microbiome is affected beyond clinical recovery.


Review: intrahepatic cholestasis. A puzzling disorder of pregnancy.
Intrahepatic cholestasis of pregnancy is characterized by skin pruritus and a biochemical cholestasis of mild to moderate severity appearing during pregnancy (mainly in the third trimester) and disappearing after delivery. It recurs in 40-60% of future pregnancies. The intensity of pruritus and the laboratory alterations (increased serum bile salts and transaminases in almost all patients, hyperbilirubinaemia in 20% of patients) fluctuate during one pregnancy and also vary in subsequent affected pregnancies. This disease has no meaningful consequences for the mother; in contrast, it is associated with an increased risk of foetal distress, causing premature deliveries and stillbirths. Cholestasis of pregnancy has been recognized in most countries and ethnic groups but its prevalence is higher in Chile (14% of deliveries in 1975 and approximately 4% in 1995) and in Sweden than in other countries. The cause in unknown. Sex hormones, mainly oestrogens and progesterone, appear to be involved in its pathogenesis. An interplay between a genetic metabolic predisposition and some environmental factor(s) is apparently relevant. Clinical and experimental studies suggest that a marginal selenium deficiency could be a dietary pathogenic factor. Some drugs attenuate pruritus and improve maternal cholestasis, but not the foetal prognosis. Ursodeoxycholic acid (UDCA) administration provides a significant improvement in maternal pruritus and in the biochemical abnormalities, with no adverse effects in the mother or child. Recent clinical and experimental studies show that UDCA administration improves maternal disease and foetal prognosis without any detectable adverse effects.


Time spent outdoors at midday and children's body mass index.
We investigated whether the Kidskin sun protection intervention increased children's body mass index by reducing the time spent outdoors at midday. The Kidskin sun protection intervention involved 1614 Australian school children assigned to 1 of 3 groups: a control group, a moderate-intervention group, or a high-intervention group. Schools in the control group received the standard health curriculum and schools in the intervention groups received a multicomponent intervention. Outcomes included time spent outdoors and nevus development (a marker of melanoma risk). Height and weight were measured at 3 time points. Body mass index was transformed into age- and gender-specific z scores; z scores at each age were modeled simultaneously. Time spent outdoors at ages 10 and 12 years was analyzed using a linear mixed effects modeling. The proportion of children who were overweight or obese increased with age. The moderate-intervention and control groups had a minimal increase in z score over time, and the z score for the high-intervention group decreased over time. There were no differences among groups with respect to total time outdoors at any age. It is possible to reduce the time children spend outdoors when ultraviolet radiation is high without producing an unfavorable effect on the children's body mass index.


Histone deacetylase inhibitors regulate vitamin C transporter functional expression in intestinal epithelial cells.
Intestinal absorption of vitamin C in humans is mediated via the sodium-dependent vitamin C transporters (hSVCT1 and hSVCT2). hSVCT1 and hSVCT2 are localized at the apical and basolateral membranes, respectively, of polarized intestinal epithelia. Studies have identified low plasma levels of vitamin C and decreased expression of hSVCT1 in patients with several inflammatory conditions including inflammatory bowel disease (IBD). Investigating the underlying mechanisms responsible for regulating hSVCT1 expression are critical for understanding vitamin C homeostasis, particularly in conditions where suboptimal vitamin C levels detrimentally affect human health. Previous research has shown that hSVCT1 expression is regulated at the transcriptional level, however, little is known about epigenetic regulatory pathways that modulate hSVCT1 expression in the intestine. In this study, we found that hSVCT1 expression and function were significantly decreased in intestinal epithelial cells by the histone deacetylase inhibitors (HDACi), valproic acid (VPA), and sodium butyrate (NaB). Further, expression of transcription factor HNF1α, which is critical for SLC23A1 promoter activity, was significantly down regulated in VPA-treated cells. Chromatin immunoprecipitation (ChIP) assays showed significantly increased enrichment of tetra-acetylated histone H3 and H4 within the SLC23A1 promoter following VPA treatment. In addition, knockdown of HDAC isoforms two, and three significantly decreased hSVCT1 functional expression. Following VPA administration to mice, functional expression of SVCT1 in the jejunum was significantly decreased. Collectively, these in vitro and in vivo studies demonstrate epigenetic regulation of SVCT1 expression in intestinal epithelia partly mediated through HDAC isoforms two and three.


Living arrangements of older adults in the developing world: an analysis of demographic and health survey household surveys.
This study examines living arrangements of older adults across 43 developing countries and compares patterns by gender, world regions, and macro-level indicators of socioeconomic development. Data are from Demographic and Health Surveys. The country is the unit of analysis. Indicators include household size, headship, relationship to head, and coresidence with spouse, children, and others. Unweighted regional averages and ordinary least-squares regressions determine whether variations exist. Average household sizes are large, but a substantially greater proportion of older adults live alone than do individuals in other age groups. Females are more likely than males to live alone and are less likely to live with a spouse or head of a household. Heading a household and living in a large household and with young children is more prevalent in Africa than elsewhere. Coresidence with adult children is most common in Asia and least in Africa. Coresidence is more frequent with sons than with daughters in both Asia and Africa, but not in Latin America. As a country's level of schooling rises, most living arrangement indicators change with families becoming more nuclear. Urbanization and gross national product have no significant effects. Although living arrangements differ across world regions and genders, within-region variations exist and are explained in part by associations between countrywide levels of education and household structure. These associations may be caused by a variety of intermediating factors, such as migration of children and preferences for privacy.


Plasma catecholamines and autonomic nervous system function in patients with early renal insufficiency and hypertension: effect of clonidine.
Plasma catecholamines, hand-grip exercise and orthostatic stress were used to assess sympathetic nerve function in 14 hypertensive patients with mild to moderate renal failure and, for comparison, in 14 age-matched normal subjects. Furthermore, acute and chronic administrations of clonidine were used to determine a participation of the sympathetic nervous system in the maintenance of hypertension in these patients. Baseline mean blood pressure (MBP), plasma norepinephrine (NE), plasma renin activity (PRA) and aldosterone were elevated in patients with renal failure. During hand-grip exercise, the rise in MBP and in heart rate was blunted in these patients. During orthostasis, MBP decreased more while the increments in NE were greater in hypertensive patients that in normal subjects. Acute administration of clonidine (200 micrograms orally) resulted in a significant decrease in MBP, heart rate, NE, PRA, and aldosterone. There was a significant (p less than 0.01) correlation between the decrease in NE and the fall in MBP. After 6 weeks of treatment, clonidine produced a significant decrease in MBP, heart rate, NE and aldosterone, but not in PRA. Chronic treatment with clonidine produced a slight but significant (p less than 0.05) rise in serum potassium and in serum creatinine. Exchangeable sodium and plasma volume did not change significantly. The data indicate that abnormalities in the function of the sympathetic nervous system are already evident in patients with mild to moderate renal failure. The data also suggest that the sympathetic nervous system may participate in the maintenance of the hypertension in these patients.


Physical injury: a profile among the municipal primary school children of Siliguri, Darjeeling District.
A cross sectional study was conducted from February - May 2009 with the objectives to find out profile of injuries among municipal primary school children in Siliguri, West Bengal and to identify the related factor associated with injury. 20% of total primary schools under municipal corporation of the town were selected and a pre-designed, pre-tested schedule was used to assess the profile of injury and associated factors. The Chi square test was usedto determine statistical significance at the 0.05 significance level. Out of 956 participants, a significantly higher injury was observed among males (68%). Open wound injuries were commonest (59.6%) occurring mainly at the extremities. Falls were mainly responsible for overall injuries. Injury at home (41.8%) was also found to be more. Mother education, number of siblings and presence of caregiver were significant related factors to injury.


The functional morphology of the cercopithecoid wrist and inferior radioulnar joints, and their bearing on some problems in the evolution of the Hominoidea.
The cercopithecoid wrist joint differs from the wrist joints of hominoids in several ways. The distal ulna, the distal radius, the pisiform, the triquetrum, the hamate, and the base of the fifth metacarpal are on the one hand remarkably alike among cercopithecoid genera, and on the other remarkably distinct from homologous bones in the Hominoidea. Functionally, the triquetrum and the pisiform, in conjuction with the ulnar styloid process, check the proximal carpal row during ulnar deviation, and are possibly important in stabilizing the wrist during dorsiflexion as well. The head of the ulna almost certainly betokens a range of radioulnar supination in cercopithecoids that is substantially less than is to be found in any of the hominoid genera. The articulation between the hamate bone and the base of the fifth metacarpal allows for considerable dorsiflexion in the Cercopithecoidea; this potential was not evidenct in any of the hominoids examined. Behaviorally, the cercopithecoid wrist can most profitably be viewed as an adaptation for a quadrupedal life style involving dorsiflexion of the wrist and palmigrade/digitigrade substrate contact. The hominoid wrist joint is not adapted for such a behavioral potential.


Antinociceptive effects of novel A2B adenosine receptor antagonists.
Caffeine, an adenosine A1, A2A, and A2B receptor antagonist, is frequently used as an adjuvant analgesic in combination with nonsteroidal anti-inflammatory drugs or opioids. In this study, we have examined the effects of novel specific adenosine receptor antagonists in an acute animal model of nociception. Several A2B-selective compounds showed antinociceptive effects in the hot-plate test. In contrast, A1- and A2A-selective compounds did not alter pain thresholds, and an A3 adenosine receptor antagonist produced thermal hyperalgesia. Evaluation of psychostimulant effects of these compounds in the open field showed only small effects of some antagonists at high doses. Coadministration of low, subeffective doses of A2B-selective antagonists with a low dose of morphine enhanced the efficacy of morphine. Our results indicate that analgesic effects of caffeine are mediated, at least in part, by A2B adenosine receptors.


The need for and development of an adaptive Listening and Communication Enhancement (LACE) Program.
Auditory training has long been advocated to enhance communication but has never been time or cost-effective. This article describes the concepts underlying the development of a home-based, interactive adaptive computer program designed to engage the adult hearing-impaired listener in the hearing-aid-fitting process, provide listening strategies, build confidence, and address cognitive changes characteristic of the aging process. An investigation using a between-group, within-subject design with pre- and post-test objective and subjective measures was conducted at five clinical sites. Sixty-five subjects were randomly placed into two groups, one receiving LACE (Listening and Communication Enhancement) immediately following baseline testing and one serving as a control for one month and then receiving training as a crossover group. Results showed statistically significant improvements for the trained subjects on all but one of the outcome measures. Barriers facing the widespread implementation of home-based aural rehabilitation are discussed.


Survival and Resilience Among Palestinian Women: A Qualitative Analysis Using Individual and Collective Life Events Calendars.
Responding to the need for more information concerning the mental health and psychological well-being of women living amid political oppression and war, this study aimed to explore specific factors that contribute to women's individual and collective perceptions about war and the associated traumatic life events that occurred during their lives. Moving from a socioecological and culture-informed perspective, we used narrative timelines elicited from 21 Palestinian women in Gaza, both individually and collectively, as a tool for both data collection and intervention. A deductive, top-down, thematic content analysis procedure was used to categorize data. The main events outlined by the women in their historical accounts, both individual and collective, were linked to political events in and surrounding Palestine. The life events' calendars reflect a constant attempt in balancing and compensating traumatic events with sources of well-being related to social support and family. Individual and collective narrative activities contributed to generate a significant reframing in the attribution of meaning and emotional perceptions of the participants. Women articulated how they build resilience through transgenerational and daily practices of resistance that encompass indigenous strategies of coping and skills of survival.


Pathology after eculizumab in dense deposit disease and C3 GN.
Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.


Arthrodesis of the Ankle.
About 90 % of all cases of painful posttraumatic ankle arthritis can be very successfully treated with a minor invasive ankle arthrodesis technique by using a small anterior approach and a fixation with four 6. 5 mm screws of which the posteromedial and transfibular one are inserted percutaneously. The results with this standardized procedure have been reported previously as excellent and good in a mid-term run of 6 years (34). This technique leads to a high union rate of 99% (92 of 93) with rapid bone healing within 8 ± 2 weeks, it causes a low minor complication rate of 8 % and enables a significant increase of the AOFAS ankle/hindfoot score (17) from 36 preoperatively to 85 postoperatively as well as a midtarsal movement of 24° ± 16°. In some cases of ankle arthritis due to chronic syndesmotic instability a 5th screw is additionally used to compress the reamed espace claire for regaining a stable ankle fork. A 5th screw is used also in case of necessary shortening of the fibula or in cases of idiopathic ankle arthritis with gross varus deformity when a transfibular approach becomes necessary instead of the anterior approach. About 10% of ankle arthrodesis need different procedures like in cases of malunited ankle or pilon fractures with low grade infection, larger bony defects due to resection of necrotic bone, due to primary bone loss in open fractures or due to secondary bone loss in failed ankle replacement cases. They need usually a two stage procedure with primary debridement and temporary joint transfixation and secondary anterior double plate fixation with autogenous bone grafting. In case of critical anterior soft tissues a posterolateral approach with a bladeplate-fixation is performed. In the very rare cases of severe ankle infection a three stage procedure is recommended with a radical necrectomy of infected soft tissues or dead bone and/or combined with taking biopsies, filling the defects with Gentamycin-PMMA- beads and stabilizing the reamed joint with a threaded compression Charnley fixator in the first stage. A re-debridement in the second stage might need additionally a permanent lavage with sensitive antibiotics according to the probes and in the third stage a third debridement with finally autogeneous bonegrafting is done. Key words: ankle arthrodesis, anterior, posterolateral, transfibular ankle approach, 4- to 5-screw fixation technique, double plate fixation, autogeneous bonegrafting, Charnley compression fixator.


Impact of Pharmacy-Initiated Interventions on Influenza Vaccination Rates in Pediatric Solid Organ Transplant Recipients.
In solid organ transplant (SOT) recipients, influenza infection can lead to subsequent graft dysfunction and death. Vaccination is the most effective approach to preventing influenza infection; however, vaccination rates are low, and interventions to optimize vaccine coverage are needed. The purpose of this study was to evaluate if pharmacy-initiated screening and recommendations for influenza immunization improve the rate of vaccination in pediatric SOT recipients. We performed a retrospective pre-post chart review of all kidney, liver, and heart transplant recipients followed by Children's Healthcare of Atlanta/Emory University transplant services between September 1, 2011, and February 16, 2017. Influenza vaccination coverage and influenza rates before (2011-2013) and after (2014-2016) the implementation of pharmacy-driven vaccination in SOT recipients were assessed. A total of 822 patients were included; 101 (13%) of these patients were diagnosed with influenza, and 40 (5%) were hospitalized secondarily during the study period. Vaccination coverage increased over time (144 [36%] patients vaccinated in 2011 vs 430 [74%] in 2016; P < .001). Influenza diagnosis rates decreased between the 2 eras (P = .006). The median time in which 50% of the population was vaccinated decreased over time from 163 days in 2012 to 94 days in 2016 (P < .001). Within the constraints of the pre-post study design, we observed a significant increase in influenza vaccination rates after implementation of a transplant pharmacy-initiated screening and vaccination program. The number of patients diagnosed with influenza and the time to vaccination decreased after our pharmacy intervention. All efforts should be made to increase compliance with influenza vaccination; pharmacy-initiated interventions can improve protection against influenza infection in pediatric SOT recipients.


Synthetic approaches to the polycyclic alkaloid stemofoline.
Preliminary studies of a synthetic approach to the alkaloid stemofoline 1 are reported. Stereoselective cyclisation of the ketoester 14 gave the 1-butyl-2,8-bis(methoxycarbonyl)-8-azabicyclo[3.2.1]octane 21 in which the 2-methoxycarbonyl group is in the axial position. The analogous ketones 15, 18, and 19 were also cyclised to give the 8-azabicyclo[3.2.1]octanes 22-24 with axial electron-withdrawing 2-substituents. The structure of the bicyclic ketosulfone 22 was confirmed by X-ray diffraction. Conversion of ester 21 into the tricyclic lactams 31 and 39, in which the amide fragments are significantly distorted from planarity, was achieved by treatment of the iodides 29 and 38 with tert-butyllithium. The structure of the deprotected tricyclic hydroxylactam 40 was confirmed by X-ray diffraction, which showed the non-planar geometry of the lactam fragment and the distortion induced into the bicyclo[3.2.1]octane by the additional two-carbon bridge. This meant that the endo hydrogen at C9 was significantly closer to the 5-hydroxyl group than the endo hydrogen at C8. This structural feature was utilised to direct a regioselective remote oxidation of the hydroxylactam 40 using lead tetraacetate, which was accompanied by selective insertion into the closer endo C-H bond to give the tetracyclic ether 41. Lactam 39 was converted into the tricyclic aminoketone 49 by reduction to the aminol 44 using lithium aluminium hydride and reduction of the intermediate, possibly the chloride 46, formed from aminol 44 using thionyl chloride, with more lithium aluminium hydride, followed by O-deprotection and oxidation. The bicyclic ketoester 21 was also protected as its ketal 50, which was taken through via the tricyclic lactam 54 into the ketoamine 49. Finally, allylation of the tricyclic lactam 42 and amine 49 gave the axial allylated products 60 and 58, but further elaboration for incorporation of C10 and C11 (of stemofoline) was not straightforward. Alkylation of the protected hydroxyketone 64, which was prepared from the bicyclic ketoester 21, gave the axial alkylated products 65 and 69, and the ketoester 69 was converted into the tricyclic hydroxylactone 73. However, the formation of a tetracyclic lactam by treatment of the iodide 75 with tert-butyllithium was not successful.


Effect of including torsional parameters for histidine-metal interactions in classical force fields for metalloproteins.
Classical force-field parameters of the metal site of metalloproteins usually comprise only the partial charges of the involved atoms, as well as the bond-stretching and bending parameters of the metal-ligand interactions. Although for certain metal ligands such as histidine residues, the torsional motions at the metal site play an important role for the dynamics of the protein, no such terms have been considered to be crucial in the parametrization of the force fields, and they have therefore been omitted in the parametrization. In this work, we have optimized AMBER-compatible force-field parameters for the reduced state of the metal site of copper, zinc superoxide dismutase (SOD1) and assessed the effect of including torsional parameters for the histidine-metal interactions in molecular dynamics simulations. On the basis of the obtained results, we recommend that torsion parameters of the metal site are included when processes at the metal site are investigated or when free-energy calculations are performed. As the torsion parameters mainly affect the structure of the metal site, other kinds of structural studies can be performed without considering the torsional parameters of the metal site.


[Characterization of children and adolescents with type 1 diabetes in therapeutic follow-up].
This descriptive study with mothers of children and adolescents carriers of diabetes type 1, aims to characterize these children and adolescents enrolled in elementary and high school, either public or private, while in therapy. To reach our purposes, we used direct interviews whose results led us to the following conclusions: most of them (83%) have been carriers of the disease for more than five years; 93.3% had been submitted to hospital treatment, considering hypoglycemia as the most frequent reason (46.7%). It also points toward the need to develop equity while caring for the family of children and adolescents with diabetes type 1, giving them support to cope with the child carrier of a chronic disease.